Interferon alpha signalling and its relevance for the upregulatory effect of transporter proteins associated with antigen processing (TAP) in patients with malignant melanoma

Introduction: Interferon alpha (IFNα) is routinely used in the clinical practice for adjuvant systemic melanoma therapy. Understanding the molecular mechanism of IFNα effects and prediction of response in the IFNα therap
Introduction: Interferon alpha (IFNα) is routinely used in the clinical practice for adjuvant systemic melanoma therapy. Understanding the molecular mechanism of IFNα effects and prediction of response in the IFNα therapy regime allows initiation and continuation of IFNα treatment for responder and exclusion of non-responder to avoid therapy inefficacy and side-effects. The transporter protein associated with antigen processing-1 (TAP1) is part of the MHC class I peptide-loading complex, and important for antigen presentation in tumor and antigen presenting cells. In the context of personalized medicine, we address this potential biomarker TAP1 as a target of IFNα signalling.
Results: We could show that IFNα upregulates TAP1 expression in peripheral blood mononuclear cells (PBMCs) of patients with malignant melanoma receiving adjuvant high-dose immunotherapy. IFNα also induced expression of TAP1 in mouse blood and tumor tissue and suppressed the formation of melanoma metastasis in an in vivo B16 tumor model. Besides its expression, TAP binding affinity and transport activity is induced by IFNα in human monocytic THP1 cells. Furthermore, our data revealed that IFNα clearly activates phosphorylation of STAT1 and STAT3 in THP1 and A375 melanoma cells. Inhibition of Janus kinases abrogates the IFNα-induced TAP1 expression. These results suggest that the JAK/STAT pathway is a crucial mediator for TAP1 expression elicited by IFNα treatment.
Conclusion: We suppose that silencing of TAP1 expression provides tumor cells with a mechanism to escape cytotoxic T-lymphocyte recognition. The observed benefit of IFNα treatment could be mediated by the shown dual effect of TAP1 upregulation in antigen presenting cells on the one hand, and of TAP1 upregulation in ‘silent’ metastatic melanoma cells on the other hand. In conclusion, this work contributes to a better understanding of the mode of action of IFNα which is essential to identify markers to predict, assess and monitor therapeutic response of IFNα treatment in the future.
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Metadaten
Author:Ruth Heise, Philipp M. Amann, Silke Ensslen, Yvonne Marquardt, Katharina Czaja, Sylvia Joussen, Daniel Beer, Rupert Abele, Gabriele Plewnia, Robert Tampé, Hans Merk, Heike Margarete Hermanns, Jens Malte Baron
URN:urn:nbn:de:hebis:30:3-392661
DOI:http://dx.doi.org/10.1371/journal.pone.0146325
ISSN:1932-6203
Parent Title (English):PLoS One
Place of publication:Lawrence, Kan.
Document Type:Article
Language:English
Date of Publication (online):2016/01/06
Date of first Publication:2016/01/06
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/02/04
Volume:11
Issue:(1): e0146325
Pagenumber:19
First Page:1
Last Page:19
Note:
Copyright: © 2016 Heise et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
HeBIS PPN:377742961
Institutes:Biochemie und Chemie
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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